Sexual response in women is generally classified into four stages: excitement, plateau, orgasm, and resolution. Masters and Johnson, Human Sexual Response (Little, Brown & Co., Boston, Mass. 1966). With sexual arousal and excitement, vasocongestion and muscular tension increase progressively, primarily in the genitals, and is manifested by increased blood flow, elevated luminal oxygen tension, and vaginal surface lubrication as a result of plasma transudation that saturates the fluid reabsorptive capacity of the vaginal epithelium. Vasoactive intestinal polypeptide (“VIP”) release may induce the physiological changes of sexual arousal and excitement, and may be the major neurotransmitter effecting neurologically controlled increase of the vaginal blood supply upon arousal. The peptide histidine methionine has been co-located with VIP within nerve fibers that innervate small blood vessels, smooth muscle, and epithelial cells in the vaginal tract.
VIP is a neurotransmitter known to effect small vessel dilation in the mesenteric blood supply in response to mechanical sensation of food in the gut to promote digestion. VIP is therefore found in the cholinergic, parasympathetic ganglia of the intestinal peripheral nervous system. Kandel, Schwartz, and Jessel, Principles of Neural Science, 4th ed. (McGraw-Hill 2000). VIP was initially discovered, isolated and purified from porcine intestine, and the twenty-eight (28) amino acid VIP has extensive homology to secretin and glucagon (Carlquist et al., Horm. Metab. Res. 14:28–29 (1982)). VIP is known to exhibit a wide range of biological activities in the gastrointestinal tract and circulatory system. VIP has been shown to stimulate pancreatic and biliary secretion, hepatic glycogenolysis, glucagon and insulin secretion and to activate pancreatic bicarbonate release (Kerrins t al., Proc. Soc. Exp. Biol. Med. 142:1014–1017 (1972); Domschke et al., Gastroenterology 73:78–480 (1977)).
The physiologic effects of VIP extend outside the digestive system. For example, neurons containing VIP have been localized by immunoassay in cells of the endocrine and exocrine systems, intestine and smooth muscle (Polak et al., Gut 15:720–724 (1974)), and has been found to be a neuroeffector of the release of hormones including prolactin (Frawley et al., Neuroendocrinology 33:79–83 (1981)), thyroxine (Ahren et al., Nature 287:343–345 (1980)), and the aforementioned insulin and glucagon (Schebalin, et al., Am. J. Physiology E. 232:197–200 (1977). VIP is present in neurons and neural junctions in the airways of animal species including man (Dey et al., Fed. Proc. 39:1062 (1980); Said et al., Ann. N.Y. Acad. Sciences 221:103–114 (1974)). VIP has also been found to stimulate renin release from the kidney in vivo and in vitro (Porter et al., Neuroendocrinology 36:404–408 (1983)), and the presence of VIP in other parts of the genito-urinary system has been shown. The widely appreciated direct vasoactive effect of VIP is to increase blood flow into capillary bed by dilation of the afferent blood vessel. Various analogs of VIP, both agonistic and antagonistic are known to exist (see, e.g., U.S. Pat. Nos. 5,235,907, 5,141,924, 4,734,400 and 4,605,641 to Bolin; and U.S. Pat. Nos. 4,939,224 and 4,835,252 to Musso et al.).
Sexual excitement is initiated by any of a number of psychogenic or somatogenic stimuli and must be reinforced to result in orgasm. With continued stimulation, excitement progresses in intensity into a plateau stage, from which the individual can shift into orgasm. The orgasmic stage is characterized by a rapid release from vasocongestion and muscular tension.
During the various stages of sexual response, characteristic genital and extragenital responses occur. Estrogens magnify the sexual responses; however, sexual responses may also occur in estrogen-deficient individuals. Sexual dysfunction may be due to organic or functional disturbances. For example, a variety of diseases affecting neurologic function, including diabetes mellitus and multiple sclerosis, may interrupt sexual arousal. More commonly, local pelvic disorders, such as endometriosis and vaginitis, both of which cause dyspareunia (difficult or painful coitus) may also affect a woman's sexual response. In addition, estrogen deficiency, causing vaginal atrophy and dyspareunia, is a common cause of sexual dysfunction. For a discussion of other causes of female sexual dysfunction, see, e.g., Kaplan, The Evaluation of Sexual Disorders: Psychological and Medical Aspects (Brunner-Mazel, New York, N.Y. 1983), and Kolodny et al., Textbook of Sexual Medicine (Little, Brown & Co., Boston, Mass. 1979).
Excitement stage dysfunction generally involves touch sensation impairment, loss of clitoral sensation, vaginal dryness, and urinary incontinence. Such excitement phase dysfunction generally results in dyspareunia. Dyspareunia is thought to affect approximately 40% of women, due in large part to inadequate lubrication. It has been estimated that over 40 million women will suffer dyspareunia at some time in their lives. On the order of twenty-five million women will experience dyspareunia in the peri- and postmenopausal period (see, Kelly, Clinical Practice and Sexuality 8(8):2 (1992) and Sato et al., Clinical Practices in Sexuality 8(5):1 (1992)). Contemporary symptomatic treatments generally involve the use of physiologically safe lubricants such as egg white, K-Y surgical lubrication jelly (hydroxyethyl-cellulose), ASTROGLIDE® (Astro-Lube, Inc., N. Hollywood, Calif.), and REPLENS® (Columbia Laboratories, Inc., Aventura, Fla.). See, e.g., Semmens, Medical Aspects of Human Sexuality 8:85–86 (1974); and Frishmen et al., Fertility and Sterility 58(3):630 (1992). When symptomatic treatment fails, pharmacological treatment may be indicated.
Estrogen therapy is commonly used in the pharmacological treatment of sexual dysfunction in women. Estrogen-based therapies are generally used to increase mucous production, provide vasodilatory effects, or to increase the general health of the vagina. Nadelson et al. (eds.), Treatment Interventions in Human Sexuality (Plenum Press, New York 1983). In such treatments, estrogen is administered orally, parenterally (e.g., by injection), or topically. With oral administration, the estrogen concentration encountered by the liver is generally four- to five-fold greater than estrogen levels in peripheral blood (the “first pass effect”). This effect may lead to an undesirable increase in the production of certain coagulation factors and renin substrates by the liver. Parenterally administered estrogen avoids the first pass effect in the liver. However, all estrogen-based therapies are known to increase the risk of endometrial hyperplasia, endometrial cancer and breast cancer in treated individuals.
Because of the increased risk of endometrial hyperplasia and endometrial cancer encountered with unopposed estrogen therapies, estrogen/progestogen combinations have been employed. However, progestogens are known to have some androgenic activity. Further, common side effects from such therapies include uterine bleeding and the continuation of menstrual periods. Accordingly, there remains a need in the art to provide safer and more ways of treating female sexual dysfunction.
The present invention is directed to the aforementioned need in the art, and provides a new, highly effective method of treating sexual dysfunction in women. The method involves vaginal and/or vulvar administration of a pharmaceutical formulation containing a vasoactive agent, e.g., a prostaglandin, VIP or a VIP agonist or the like.
Drug therapy for treating female sexual dysfunction has been described. For example, U.S. Pat. No. 4,507,323 to Stem describes the use of the anxiolytic m-chloro-α-t-butylamino-propiophenone in the treatment of sexual dysfunction in both male and female individuals. Pharmaceutical compositions containing the agent are described, which are presented in discrete units, e.g., cachets, tablets, capsules, ampules and suppositories, for oral or rectal delivery of the agent.
Additionally, U.S. Pat. No. 4,521,421 to Foreman describes the treatment of sexual dysfunction in male and female individuals using the stereoisomers of octahydropyrimido[4,5-g]quinolines, centrally acting dopamine agonists.
U.S. Pat. No. 5,190,967 to Riley describes the treatment of sexual disorders in male and female individuals using heterocyclic benzodioxinopyrrole compounds, which, like the drugs described in the aforementioned patents, are centrally acting agents.
U.S. Pat. No. 5,565,466 to Gioco et al., U.S. Pat. No. 5,731,339 to Lowrey, and U.S. Pat. No. 5,773,457 to Nahoum pertain to methods for modulating the human sexual response, with the Gioco et al. and Lowrey patents emphasizing the utility of phentolamine as an active agent.
A number of references describe various methods and devices suitable for vaginal or uterine drug administration, and may accordingly be of some interest with respect to the present invention. The following are representative of such references:
U.S. Pat. No. 3,967,618 to Zaffaroni describes an intrauterine device adapted for drug delivery. A number of drugs are mentioned as being suitable for use in conjunction with the device. However, the patent does not mention treatment of sexual dysfunction, nor is application of a drug-containing composition to the clitoris or vulvar region disclosed or suggested. U.S. Pat. No. 3,948,254 to Zaffaroni is a related patent that describes an intrauterine device for continuous administration of a contraceptive agent.
U.S. Pat. No. 4,014,987 to Heller et al. describes a tampon-like device for delivery of a drug to the uterus or vagina. Heller et al. mention that delivery of prostaglandins is a preferred use of the invention; however, there is no disclosure concerning treatment of sexual dysfunction or delivery to the vulvar area.
U.S. Pat. No. 4,564,362 to Burnhill describes a vaginal sponge for controlled release of a contraceptive agent.
U.S. Pat. No. 4,112,942 to Scaife generally describes vaginal administration of medicinal foams.
There are, accordingly, a number of background references relating to treatment of female sexual dysfunction, and cervical or uterine administration of vasoactive agents. However, the present method for treating female sexual dysfunction, by way of vaginal and/or vulvar delivery of a vasoactive agent such as a prostaglandin or VIP or a receptor agonist thereof, is completely novel and unsuggested by the art.